The compound artemisinin, also known as qinghaosu (III), is a tetracyclic 1,2,4-trioxane occurring in Artemisia annua and is described in U.S. Pat. No. 4,920,147 to McChesney et al. Artemisinin and its derivatives dihydroartemisinin (DHA) (IV), artemether (V) and artesunate (VI) (FIG. 1) have been used primarily for the treatment of malaria, as described in U.S. Pat. No. 6,306,896 to Scheiwe.
Chemical studies on artemisinin and its synthetic derivatives indicate that a cause of instability is the facile opening of the trioxane moiety in artemisinin, or in its derivative dihydroartemisinin. Ring opening provides the free hydroperoxide, which is susceptible to reduction. Removal of this group ensures destruction of drug activity with the reduction products being transformed into desoxo metabolites. In order to render ring-opening less facile, the oxygen atom at C-10 can be either removed to provide 10-deoxydihydroartemisinin, or replaced by other groups. This has provided the basis for the so-called “second generation” compounds which are generally 10-deoxy artemisinin derivatives. In addition, derivatives of artemisinin with a variety of substituents at C-9 have also been prepared.
Artemisinin derivatives in which the oxygen atom at C-10 is replaced by an amine group have been produced. For instance, Yang et al. (Biorg. Med. Chem. Lett., 1995, 5, 1791-1794) synthesized ten new artemisinin derivatives in which the oxygen atom at C-10 was replaced by —NHAr, where Ar represents a phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-carboxylphenyl or 4-carboxylphenyl group. These compounds were tested for in vivo activity against the K173 strain of Plasmodium berohei and were found to be active.
U.S. Pat. No. 6,984,640 and United States patent application 2005/0119232 disclose certain C-10 substituted derivatives of artemisinin that are disclosed to be effective in the treatment of diseases caused by infection with a parasite of the genera Plasmodium, Neospora or Eimeria, especially Plasmodium falciparum, Neospora caninum and Eimeria tenella, which cause malaria, neosporosis and coccidiosis, respectively. The disclosed compounds are of the general formula I:
or a salt thereof, in which Y represents a halogen atom, an optionally substituted cycloalkyl, aryl, C-linked heteroaryl or heterocyclylalkyl group or a group —NR1R2; where R1 represents a hydrogen atom or an optionally substituted alkyl, alkenyl or alkynyl group; R2 represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group; or R1 and R2 together with the interjacent nitrogen atom represent an optionally substituted heterocyclic group or an amino group derived from an optionally substituted amino acid ester; for use in the treatment and/or prophylaxis of a disease caused by infection with a parasite.
Artemisinin derivatives, artemisone and especially artemiside have been shown by Dunay et al. (Antimicrob Agents Chemother. 2009, 53(10), 4450-4456) to display enhanced inhibition of Toxoplasma gondii, and by Guo et al. (Antimicrob Agents Chemother. 2012, 56(1), 163-173) to have a pronounced effect on Plasmodium falciparum. Artemisone differs from currently used clinical artemisinins in that it does not elicit neurotoxicity in preclinical in vitro and in vivo screens. In a pilot tolerability test, treatment of male rats with artemisone at 50 mg/kg for 14 days had no effect as compared to controls. Studies involving proliferation of human endothelial cells and generation of new vessels, indicate that artemisone is significantly less anti-angiogenic than dihydroartemisinin, suggesting that it might be safer to use artemisone during pregnancy (D'Alessandro et al., Toxicology, 2007, 241, 66-74). Newer polar derivatives including the urea derivative RW177 have also been shown to have sub-nanomolar activity against the malarial parasite (see FIG. 1 for the structures of the derivatives).
U.S. Pat. No. 6,649,647 to one of the inventors of the present invention, discloses compounds containing a trioxane moiety, especially certain artemisinin derivatives, which have cytotoxic and anti-tumor activity and their use in the treatment of cancer. Some of these compounds comprise a ligand which is capable of binding to a nucleic acid and a group containing a trioxane moiety which is capable of acting as source of free radicals which are capable of chemically interacting with a nucleic acid. Processes for the preparation of such compounds and pharmaceutical compositions containing such compounds are also provided.
Viral infections account for a very large fraction of infectious disease mortality and morbidity worldwide. Cytomegalovirus (CMV), for example, a beta herpesvirus, is a major cause of morbidity and mortality in immunocompromised individuals including AIDS patients and recipients of hematopoietic stem cell transplantation (HSCT) or solid organ transplants. CMV is also the leading cause of congenital infection, affecting ˜1% of live births, with resultant neurological damage and loss of hearing. Despite the considerable public health burden of congenital CMV, no established prenatal antiviral treatments are available.
In a transplantation setting, the widespread use of preventive antiviral therapy has reduced the occurrence of early CMV disease; however, the development of late disease is increasingly recognized. Preventive antiviral strategies include (a) preemptive therapy in patients who become positive for CMV antigen or CMV DNA in the blood after transplantation and (b) universal prophylaxis initiated in all at-risk patients at the time of engraftment and continued until 100 days after transplantation.
All currently available anti-CMV drugs, including ganciclovir, foscarnet and cidofovir, target the viral DNA polymerase. Although these drugs are effective, their use is limited by toxicity, low oral bioavailability, high cost, and teratogenicity.
Additionally, prolonged or repeated antiviral treatment may lead to the development of drug resistance and occasionally cross-resistance to multiple drugs.
Artemisinin derivatives have been suggested for the treatment of viral infections. United States patent application 2008/0161324 suggests that artemisinins may be useful in combination with other agents in treating viral diseases. Artesunate has been shown to inhibit the replication of cytomegalovirus (CMV) (Efferth et al., J. Mol. Med., 2002, 80(4), 233-242) and has been used to treat CMV infection (Shapira et al., Clin. Infect. Dis., 2008, 46(9), 1455-1457).
None of the above references discloses or suggests use of 10-alkylamino artemisinin derivatives in treating viral infections or diseases resulting therefrom.
Thus, there is a clear need for effective and safe, anti-CMV drugs with high oral bioavailability. In addition, there remains a critical and unmet medical need for new therapeutic modes of treating viral infections.